U.S. Pat. No. 5,532,415 discloses R(+)-N-propargyl-1-aminoindan (R(+)PAI), its preparation, and various pharmaceutically acceptable salts thereof. R(+)PAI and salts thereof have been shown to be selective inhibitors of MAO-B, useful in treating Parkinson's disease and various other conditions.
Indanylamine and aminotetralin derivative compounds, such as those of Formula I below, are useful to treat depression, Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD), Tourett's Syndrome, Alzheimer's Disease and other dementias as described in PCT application publication WO98/27055. The indanylamine derivatives disclosed have been shown to have biological effects in animal models of neurological disease.
Formula I is:
wherein b is 1 or 2; m is from 0-3, Y is O or S, X is halo, R4 is hydrogen or C1-4 alkyl, R5 is hydrogen, C1-4 alkyl, or optionally substituted propargyl and R6 and R7 are each independently hydrogen, C1-8 alkyl, C6-12 aryl, C6-12 aralkyl, each optionally halo substituted.
One compound disclosed in the PCT application publication is (R)-6-(N-methyl, N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan, also known as (3R)-3-(prop-2-ynylamino)-2,3,-dihydro-1H-inden-5-yl ethylmethylcarbamate. Salts thereof are also disclosed, including a ½ L-tartrate salt. This salt has been given the nonproprietary name ladostigil tartrate. Its CAS registry number is 209394-46-7.
PCT application publication WO98/27055 also discloses methods for the preparation of indanylamine and aminotetralin derivatives of Formula I using, for example, as starting materials 3-amino-indan-5-ol or 6-methoxy-indan-1-ylamine. Methods of preparation of the starting materials are also disclosed. 6-Methoxy-indan-1-ylamine is prepared by conversion of 6-methoxy-indan-1-one to 6-methoxy-indan-1-one oxime followed by reduction to 6-methoxy-indan-1-ylamine. Alternatively 6-methoxy-1-aminoindan can be prepared by reductive amination (NaCNBH3 and NH4OAc) of 6-methoxy-indan-1-one to 6-methoxy-indan-1-ylamine. 3-Amino-indan-5-ol can be prepared by using a Friedel-Crafts acylation of an N-protected 3-aminoindan, followed by a Baeyer-Villiger oxidation with subsequent hydrolysis.
These methods for producing starting materials such as 3-amino-indan-5-ol and 6-methoxy-indan-1-ylamine are accompanied by low yields. Thus, there is a need for reliable processes to produce indanylamine and aminotetralin derivatives in high yields as intermediates to prepare aminoindan derivatives and specifically compounds of Formula I, wherein the processes are suitable for industrial production.
Additionally, there is a need for efficient ways of producing enantiomerically enriched indanylamine derivatives. The prior art does not disclose sufficiently efficient methods of enantiomeric purification. In the prior art method of optical resolution of either the starting material or of the end product via diastereomeric salt formation, the undesired enantiomer is “wasted,” and the yield is thereby decreased. Another method disclosed in the prior art, resolution using a chiral chromatographic column, is not feasible for a large scale synthesis.
Small scale asymmetric reduction of 1-indanone by transfer hydrogenation using silica-immobilized Ru-TsDPEN catalysts is described by Liu et al. Org. Lett., Vol. 6, 2004, Efficient Heterogeneous Asymmetric Transfer Hydrogenation of Ketones Using Highly Recyclable and Accessible Silica-immobilized Ru-TsDPEN Catalysts. 